N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N 2  -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N²-alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceuticallyacceptable salts thereof, which are of especial value in view of theiroutstanding antithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improvedagents for the treatment of thrombosis. The N²-(p-tolylsulfonyl)-L-arginine esters have been found to be one type ofagent which can be used and these have been found to be effective indissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971)

One family of compounds, which have been found to be particularly usefulas highly specific inhibitors of thrombin for the control of thrombosisis the N² -dansyl-L-arginine ester or amide. (Our pending U.S.application Ser. No. 496,939 filed Aug. 13, 1974, now U.S. Pat. No.3,978,045)

However, there is a continuing need for a highly specific inhibitor onthrombin for the control of thrombosis, which exhibits lower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N²-alkoxynaphthalene-sulfonyl-L-argininamides exhibit antithromboticactivity and even lower toxicity levels at the same relative potencies,as compared with the N² -dansyl-L-arginine ester or amide.

The compounds of this invention can be represented by the formula (I):##STR1## wherein R₁ is naphthyl substituted with at least one C₁ -C₅alkoxy; R₂ is C₂ -C₁₀ alkylthioalkyl; R₃ is selected from the groupconsisting of hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl and C₇ -C₁₂ aralkyl;and n is an integer of 1, 2 or 3.

Also encompassed within this invention are pharmaceutically acceptablesalts thereof.

This invention also relates to a method for inhibiting activity andsuppressing activation of thrombin in vivo, which comprises introducinginto a living body a pharmaceutically effective amount of an N²-alkoxynaphthalene-sulfonyl-L-argininamide or the pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N²-alkoxynaphthalene-sulfonyl-L-argininamides of the formula (I): ##STR2##wherein R₁ is an alkoxynaphthyl wherein the alkoxy groups have 1-5(preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy and the like.Preferred are those naphthyl groups having one or two alkoxysubstituents, when two or more alkoxy groups are present, each may bethe same or different; R₂ is alkylthioalkyl of 2-10 (preferably 2-6)carbon atoms, such as methylthiomethyl, ethylthiomethyl,propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl,2-propylthioethyl, 3-methylthiopropyl, 3-ethylthiopropyl,3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl,4-butylthiobutyl, 5-butylthiopentyl and the like; R₃ is selected fromthe group consisting of hydrogen, alkyl of 1-10 (preferably 1-6) carbonatoms, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl,decyl and the like, C₆ -C₁₀ aryl such as phenyl and naphthyl, preferablyphenyl, and aralkyl of 7-12 (preferably 7-10) carbon atoms, such asbenzyl, phenethyl and the like; and n is an integer of 1, 2 or 3.

Suitable illustrations of R₁ in the above formula (I) are5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl,4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl and6,7-diethoxy-2-naphthyl.

Suitable R₂ groups in the above formula (I) are 2-methylthioethyl,2-ethylthioethyl and 3-methylthiopropyl.

Suitable -- (CH₂)_(n) --COOR₃ groups in the above fourmula (I) arecarboxymethyl, 2-carboxyethyl, 3-carboxypropyl, ethoxycarbonylmethyl,tert-butoxycarbonylmethyl, phenoxycarbonylmethyl,benzyloxycarbonylmethyl 2-ethoxycarbonylethyl,2-tert-butoxycarbonylethyl, and 3-tert-butoxycarbonylpropyl.

Illustrative of suitable N² -alkoxynaphthalenesulfonyl-L-arginamides ofthis invention are N²-(6,7-dimethoxynaphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycineand tertbutyl ester thereof.

The pharmaceutically acceptable salts of the above compound are ofcourse also included within the scope of this invention.

The above compound is intended only to illustrate the variety ofstructures which can be used in the process of this invention, and theabove listing is not to be construed as limiting the scope of theinvention.

This typical compound is highly potent in its antithrombotic activity.

For the preparation of the compounds of this invention, various methodscan be employed depending upon the particular starting meterials and/orintermediates involved. Successful preparation of these compounds ispossible by way of several synthetic routes which are outlined below.

a. Condensation of an L-argininamide with an alkoxynaphthalenesulfonylhalide

This process may be illustrated as follows: ##STR3##

In the above formulas, R₁, R₂, R₃ and n are as defined herein above, andX is halogen.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) is prepared by thecondensation of an L-argininamide (II) with a substantially equimolaramount of an alkoxynaphthalenesulfonyl halide (III), preferably achloride.

The condensation reaction is generally effected in a suitablereaction-inert solvent in the presence of an excess of a base, such asan organic base (triethylamine, pyridine) or a solution of an inorganicbase (sodium hydroxide, potassium carbonate), at a temperature of 0° Cto the boiling temperature of the solvent for a period of 10 minutes to15 hours.

The preferred solvents for the condensation include benzene-diethylether, diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water,and the solvent is removed by such standard means as evaporation underreduced pressure to give the N²-alkoxynaphthalenesulfonyl-L-argininamide (I), which can be purified bytrituration or recrystallization from a suitable solvent, such asdiethyl ether-tetrahydrofuran, diethyl ether-methanol andwater-methanol, or may be chromatographed on silica gel.

This L-argininamides (II) starting materials required for thecondensation reaction can be prepared by protecting the guanidino and α-amino group of the arginine via nitration, acetylation, formylation,phthaloylation, trifluoroacetylation, p-methoxy-benzyloxycarbonylation,benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation ortritylation and then condensing the formed N^(G) -substituted-N²-substituted-L-argininamide with a corresponding secondary amine by sucha conventional process as the acid chloride method, azide method, mixedanhydride method, activated ester method or carbodiimide method, andthereafter selectively removing the protective group.

b. Removal of the N^(G) -substituent from an N^(G) -substituted-N²-alkoxynaphthalenesulfonyl-L-argininamide

This process may be illustrated as follows: ##STR4##

In the above formulas, R₁, R₂, R₃, X and n are as defined herein above;Y" is a protective group for the amino group, such as benzyloxycarbonylor tertbutoxycarbonyl; and Y and Y' are hydrogen and protective groupsfor the guanidino group, such as nitro, tosyl, trityl, oxycarbonyl orthe like.

At least one of Y and Y' is a protective group for the guanidino group.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) is prepared byremoving the N_(G) -substituent from an N^(G) -substituted-N²-alkoxynaphthalenesulfonyl-L-argininamide (VIII) by means of acidolysisor hydrogenolysis.

The acidolysis is generally effected by contacting the N^(G)-substituted-N² -alkoxynaphthalenesulfonyl-L-argininamide (VIII) and anexcess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogenbromide or trifluoroacetic acid, without a solvent or in a solvent, suchas an ether (tetraphydrofuran, dioxane), an alcohol (methanol, ethanol)or acetic acid at a temperature of -10° to 100° C, and preferably atroom temperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excessacid, or by trituration with a suitable solvent followed by filtrationand drying.

Because of the use of the excess acid, the products are generally theacid addition salts of the N² -alkoxynaphthalenesulfonyl-L-argininamides(I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g.,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished bythe hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g.,methanol, ethanol, tetrahydrofuran or dioxane, in the presence of ahydrogen-activating catalyst, e.g., Raney nickel, palladium, orplatinum, in a hydrogen atmosphere at a temperature of 0° C to theboiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure issufficient.

The N² -alkoxynaphthalenesulfonyl-L-argininamides (I) are isolated byfiltration of the catalyst followed by evaporation of the solvent.

The N² -alkoxynaphthalenesulfonyl-L-argininamides can be purified in thesame manner as described above.

The N^(G) -substituted-N² -alkoxynaphthalenesulfonyl-L-argininamides(VIII) starting materials can be prepared by condensing an N^(G)-substituted-N² -substituted arginine (IV) (generally the N²-substituent is a protective group for the amino group, such asbenzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a correspondingsecondary amine (V) via the azide method, mixed anhydride method,activated ester method, carbodiimido method or the like, selectivelyremoving only the N² -substituent of an N^(G) -substituted-N²-substituted argininamide (VI) by means of catalytic hydrogenolysis oracidolysis, and then condensing the thus obtained N^(G)-substituted-L-argininamide (VII) with an alkoxynaphthalenesulfonylhalide (III), preferably a chloride in the presence of a base in asolvent. These reaction conditions are as described above in thecondensation of an L-argininamide with an alkoxynaphthalenesulfonylhalide, and the removal of the N^(G) -substituent from an N^(G)-substituted-N² -alkoxynaphthalenesulfonyl-L-argininamide

c. Condensation of an N² -alkoxynaphthalenesulfonyl-L-arginyl halidewith an amine

This process may be illustrated as follows: ##STR5##

In the above formulas, R₁, R₂, R₃, X and n are as defined herein above.

The N² -alkoxynaphthalenesulfonyl-L-arginamide (I) is prepared by thecondensation of an N² -alkoxynaphthalenesulfonyl-L-arginyl halide (IX),preferably a chloride with at least an equimolar amount of a secondaryamine (V).

The condensation reaction can be carried out without an added solvent.However, satisfactory results will be obtained with the use of a solventsuch as basic solvents (dimethylformamide, dimethylacetamide, etc.) orhalogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N²-alkoxynaphthalenesulfonyl-L-arginyl halide (IX).

Preferred condensation reaction temperatures are in the range of from-10° C to room temperature. The reaction time is not critical, butvaries with the secondary amine (V) employed. In general, a period offrom 5 minutes to 10 hours is operable.

The obtained N² -alkoxynaphthalenesulfonyl-L-argininamide can beisolated and purified in the same manner as described above.

The N² -alkoxynaphthalenesulfonyl-L-arginyl halide (IX) startingmaterials required for the condensation reaction can be prepared byreacting an N² -alkoxynaphthalenesulfonyl-L-arginine with at least anequimolar amount of a halogenating agent such as thionyl chloride,phosphorous oxychloride, phosphorus trichloride, phosphorouspentachloride or phosphorus tribromide. The halogenation can be carriedout with or without an added solvent.

The preferred solvents are chlorinated hydrocarbons such as chloroformand dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N²-alkoxynaphthalenesulfonyl-L-arginine.

Preferred reaction temperatures are in the range of -10° C to roomtemperature. The reaction time is not critical, but varies with thehalogenating agent and reaction temperature. In general, a period of 15minutes to 5 hours is operable.

d. Guanidylation of an N² -alkoxynaphthalenesulfonyl-L-ornithinamide oran acid addition salt thereof.

This process may be illustrated as follows: ##STR6##

In the above formulas, R₁, R₂, R₃ and n are as difined herein above.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) is prepared byguanidylating an N² -alkoxynaphthalenesulfonyl-L-ornithinamide (X) withan ordinary guanidylating agent such as an O-alkylisourea,S-alkylisothiourea, 1-guanyl-3,5-dimethylpyrazole or carbodiimide. Thepreferred guanidylating agents are the O-alkylisourea and theS-alkylisothiourea.

The guanidylation of the N² -alkoxynaphthalenesulfonyl-L-ornithinamide(X) with the O-alkylisourea or S-alkylisothiourea is generally effectedin a solvent in the presence of a base at a temperature of from 0° C tothe boiling temperature of the solvent for a period of from 30 minutesto 50 hours.

Examples of the preferred base are triethylamine, pyridine, sodiumhydroxide and sodium methoxide.

The base is used in an amount of 0.01 to 0.1 equivalent to the N²-alkoxynaphthalenesulfonyl-L-ornithinamide.

Examples of the preferred solvent are water, water-ethanol andwater-dioxane.

After the reaction is complete, the N²-alkoxynaphthalenesulfonyl-L-argininamide (I) is isolated by evaporationof the solvent followed by removal of the excess base and the formedsalt by a water wash.

It is well recognized in the art that an ester derivative of the N²-alkoxynaphthalenesulfonyl-L-argininamide (I) wherein R³ is alkyl, canbe prepared from a carboxylic acid derivative of the N²-alkoxynaphthalenesulfonyl-L-argininamide wherein R³ is hydrogen, by theconventional esterification methods well known to those skilled in theart. It is also well recognized in the art that the carboxylic acidderivative can be prepared from the ester derivative by the conventionalhydrolysis or acidolysis methods. The conditions under whichesterification, hydrolysis or acidolysis would be carried out will beeach apparent to those skilled in the art.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) of this inventionforms acid addition salts with any of a variety of inorganic and organicacids. Some of the N² -alkoxynaphthalenesulfonyl-L-argininamidecontaining a free carboxy group, wherein R₃ is hydrogen, forms saltswith any of a variety of inorganic and organic bases. The product of thereactions described above can be isolated in the free form or in theform of salts. In addition, the product can be obtained aspharmaceutically acceptable acid addition salts by reacting one of thefree bases with an acid, such as hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic,tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic acid or the like. In a similarmanner, the product can be obtained as pharmaceutically acceptable saltsby reacting one of the free carboxylic acids with a base, such as sodiumhydroxide, potassium hydroxide, ammonium hydroxide, triethylamine,procaine, dibenzylamine, 1-ephenamine, N,N'-dibenzylethylenediamine,N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in aregeneration of the free amide.

As stated above, the N² -alkoxynaphthalenesulfonyl-L-argininamides, andthe salts thereof of this invention are characterized by highly specificinhibitory activity against thrombin as well as their substantial lackof toxicity, and therefore these compounds are useful in thedetermination of thrombin in blood as diagnostic reagents, and/or forthe medical control or prevention of thrombosis.

The antithrombotic activities of the N²-alkoxynaphthalenesulfonyl-L-argininamide of this invention werecompared with that of a known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, by determining thefibrinogen coagulation time. The measurement of the fibrinogencoagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared bydissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied byArmour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solutionin the same buffer, and 0.1 ml of a thrombin solution (5 units/ml)supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutionsin an ice bath. Immediately after mixing, the reaction mixture wastransferred from the ice bath to a bath maintained at 25° C. Coagulationtimes were taken as the period between the time of transference to the25° C bath and the time of the first appearance of fibrin threads. Inthe cases where no drug samples were added, the coagulation time was50-55 seconds

The term "concentration required to prolong the coagulation time by afactor of two" is the concentration of an active ingredient required toprolong the normal coagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factorof two for the known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100 μM.

On the other hand, the same concentration for N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinewas 5 μM.

When a solution containing an N²-alkoxynaphthalenesulfonyl-L-argininamide of this invention wasadministered intravenously into animal bodies, the high antithromboticactivity in the circulating blood was maintained for from one to threehours. The halflife for decay of the antithrombotic compounds of thisinvention in circulating blood was shown to be approximately 60 minutes;the physiological conditions of the host animals (rat, rabbit, dog andchimpanzee) were well mintained. The experimental decrease of fibrinogenin animals caused by infusion of thrombin was satisfactorily controlledby simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitonealadministration of substances of formula (I) in mice (male, 20 g) rangefrom about 1,000 to 10,000 milligrams per kilogram of body weight.Representative LD₅₀ values, for example, for N²-(6,7-dimethoxynaphthalenesulfonyl)-L-arginyl-N-(2-ethylethioethyl)glycineis >1,000 milligrams per kilogram.

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide andN² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams perkilogram, respectively.

The therapeutic agents of this invention may be administered alone or incombination with pharmaceutically acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard pharmaceuticalpractice. For example, the compounds may be injected parenterally, thatis, intramuscularly, intravenously or subcutaneously. For parenteraladministration, the compounds may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic. The compounds may be administeredorally in the form of tablets, capsules, or granules containing suitableexcipients such as starch, lactose, white sugar and the like. Thecompounds may be administered sublingually in the form of troches orlozenges in which each active ingredient is mixed with sugar or cornsyrups, flavoring agents and dyes, and then dehydrated sufficiently tomake the mixture suitable for pressing into solid form. The compoundsmay be administered orally in the form of solutions which may containcoloring and flavoring agents.

Physicians will determine the dosage of the present therapeutic agentswhich will be most suitable, and dosages vary with the mode ofadministration and the particular compounds chosen. In addition, thedosage will vary with the particular patient under treatment.

When the composition is administered orally, a larger quantity of theactive agent will be required to produce the same effect as caused witha smaller quantity given parenterally. The therapeutic dosage isgenerally 10-50 mg/kg of active ingredient parenterally, 10-500 mg/kgorally per day.

Having generally described the invention, a more complete understandingcan be obtained by reference to a specific example, which is includedfor purposes of illustration only and is not intended to be limitingunless otherwise specified.

EXAMPLE A. N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloridehydrochloride

A suspension of 2.50 g of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine in 70 ml of thionylchloride containing a few drops of dimethyl formamide was stirred for 2hours at room temperature.

Addition of cold dry diethyl ther resulted in a precipitate which wascollected by filtration and washed several times with dry diethyl etherto give N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloridehydrochloride.

B. N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinetert-butyl ester

To a stirred solution of 4.80 g of N-(2-ethylthioethyl)-glycinetert-butyl ester in 40 ml of chloroform was carefully added N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochlorideobtained above. The reaction mixture was allowed to stand at roomtemperature overnight. The reaction mixture was washed twice with 20 mlof saturated sodium chloride solution and evaporated to dryness.

The residue was triturated with a small amount of water to give apowder. This was collected by filtration and reprecipitated withethanol-diethyl ether to give 5.00 g of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinetert-butyl ester.

I. R. (KBr): 3,350, 1,745, 1,650, 1,360 cm⁻ ¹. Analysis - Calcd. for C₂₈H₄₃ O₇ N₅ S. 1/2H₂ SO₃ (percent): C, 50.43; H, 6.65; N, 10.50; S, 12.02Found (percent): C, 50.57; H, 6,58; N, 10.71; S, 11.88

C. N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine

A solution of 5.0 g of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinetert-butyl ester in 10 ml of trifluoroacetic acid was stirred for 5hours at room temperature. At the end of this period, the reactionmixture was evaporated to dryness. The residue was washed several timeswith dry diethyl ether and chromatographed on 80 ml of Daiaion SK 102ion exchange resin (200-300 mesh, H⁺ form, manufactured by MitsubishiChemical Industries Limited) packed in water, washed with water andeluted with ethanol-H₂ O-NH₄ OH (5:4:1).

The main fraction eluted from the ethanol-H₂ O-NH₄ OH solution wasevaporated to dryness to give a crystalline material.

This was recrystallized from water to give 1.2 g of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-ethylthioethyl)glycine, M.P.171°-2° C.

I. R. (KBr): 3,400, 1,635, 1,260, 1,160 cm⁻ ¹ Analysis-Calcd. for C₂₄H₃₅ O₇ N₅ S₂ (percent): C, 50.60; H, 6.19; N, 12.29; S, 11.26 Found(percent): C, 50.51; H, 6.30; N, 12.40; S, 11.11

The following compounds are prepared in a similar manner:

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycineethyl ester

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylethioethyl)-.beta.-alanine

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)-.beta.-alanineethyl ester

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methylthioethyl)-N-(3-carboxypropyl)-L-argininamide

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methylthioethyl)-N-(3-tert-butoxycarbonylpropyl)-L-argininamide

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(3-methylthiopropyl)glycine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(3-methylthiopropyl)glycinetert-butyl ester

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)-.beta.-alaine

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)-.beta.-alaninetert-butyl ester

N²-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycineethyl ester

N²-(6,7-diethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(6,7-diethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycinetert-butyl ester

N²-(6-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(6-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycinetert-butyl ester

N²-(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycineethyl ester

N²-(5-methoxy-1-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(5-methoxy-1-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)glycinetert-butyl ester

N²-(5-methoxy-1-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)-β-alanine

N²-(5-methoxy-1-naphthalenesulfonyl)-L-arginyl-N-(2-methylthioethyl)-β-alaninetert-butyl ester

N²-(6,7-dimethoxynaphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinephenyl ester

N²-(6,7-dimethoxynaphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinebenzyl ester

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

What is claimed as new and intended to be covered by letters patentis:
 1. N² -alkoxynaphthalenesulfonyl-L-argininamides having the formula:##STR7## and the pharmaceutically acceptable salts thereof, wherein R₁is naphthyl substituted with at least one C₁ -C₅ alkoxy; R₂ is C₂ -C₁₀alkylthioalkyl; R₃ is hydrogen, and n is an integer of 1, 2 or
 3. 2. Thecompound of claim 1, wherein R₁ is naphthyl substituted with one or twoC₁ -C₃ alkoxy; R₂ is C₂ -C₆ alkylthioalkyl; R₃ is hydrogen.
 3. Thecompound of claim 1, wherein R₁ is selected from the group consisting of5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl,4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl and6,7-diethoxy-2-naphthyl; R₂ is selected from the group consisting of2-methylthioethyl, 2-ethylthioethyl and 3-methylthiopropyl; and R₃ ishydrogen.
 4. The compound of claim 3, which is N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)-glycine.5. A method for inhibiting activity and suppressing activation ofthrombin in vivo which comprises introducing into a living body apharmaceutically effective amount of an N²-alkoxynaphthalenesulfonyl-L-argininamide having the formula: ##STR8##or the pharmaceutically acceptable salts thereof, wherein R₁ is naphthylsubstituted with at least one C₁ -C₅ alkoxy; R₂ is C₂ -C₁₀alkylthioalkyl; R₃ is hydrogen, and n is an integer of 1, 2 or 3.